Cyclooxygenase 2Polymorphism (Val511Ala), Nonsteroidal Anti-inflammatory Drug Use and Breast Cancer in African American Women

Abstract

IntroductionNonsteroidal anti-inflammatory drugs (NSAID) have been associated with reduced risks of colon cancer, breast cancer, and other cancer sites (1, 2). We previously reported a strong inverse relationship between NSAID use and breast cancer in a North Carolina study, with a suggestion of stronger associations among African Americans (3). One hypothesized mechanism for the reduction in cancer risk by NSAIDs is the inhibition of cyclooxygenase 2 (COX2), which is overexpressed in various cancer types and is thought to stimulate angiogenesis and inhibit apoptosis (1).A polymorphism in the COX2 gene [valine to alanine at residue 511 (Val 511 Ala)] has been identified in African Americans that results in a conformation change in the enzyme near its active site, and it has been hypothesized this polymorphism could modify biochemical function or change the response to NSAIDs (4, 5). In a recent paper, carriers of this polymorphism seemed to be at reduced risk for colon adenomas [odds ratio (OR), 0.56; 95% confidence interval (95% CI), 0.25-1.27] and colon cancer (OR, 0.67; 95% CI, ref. 5). In this report, we describe the relationship between the COX2 Val 511 Ala polymorphism, NSAIDs, and breast cancer in a case-control study in North Carolina. Materials and MethodsThese analyses were based on 1,441 African American participants in the Carolina Breast Cancer Study, a population-based, case-control study conducted between 1993 to 2001 (3, 6). Cases were 20 to 74 years old and had either invasive breast cancer or carcinoma in situ. Control women were selected from Division of Motor Vehicle and Health Care Financing Administration lists and matched by race and age to cases.Genotyping was done according to previously described procedures using the Taqman system (6). The Ala 511 (C) allelespecific probe was labeled on the 5Vend with the VIC reporter dye and contained the nucleotide sequence 5V-TGCTCCAgCTTCTAC-3Vwith a melting temperature of 68.5jC and a G-C content of 53.3%. The Val 511 (T) allele-specific probe was labeled on the 5V end with the 6-FAM reporter dye and contained the nucleotide sequence 5V-TGCTCCAaCTTCTAC3Vwith a melting temperature of 67.5jC and a G-C content of 46.7%. Both probes were minor groove binding and used a nonfluorescing quencher on the 3V end. Forward and reverse primers were used to amplify the region surrounding the Val 511 Ala polymorphism. The nucleotide sequences for the forward and reverse primers were 5V-AGAAAAGCCTCGGC-CAGATG-3V and 5V-GGCAGGAGAACATATAACATTACC-CATAA-3V, respectively.Logistic regression analyses were done using the GENMOD procedure in SAS (Cary, NC). We calculated ORs and 95% CIs to evaluate the association between breast cancer and the Val 511 Ala polymorphism and the joint effects of NSAIDs and genotype. ResultsGenotyping results were available for 763 cases (673 invasive and 90 in situ) and 678 controls. The frequency of the Ala allele was 4.3% in cases and 4.0% in controls (Table 1), which is very similar to the allele frequency of 4.5% reported by Lin et al. (5)...

Current evidence on the relationship between polymorphisms in the COX-2 gene and breast cancer risk: a meta-analysis

“…A total of 10 publications (10,482 cases and 12,732 controls) met the inclusion criteria [8,[17][18][19][22][23][24][25][26][27] ( Table 1). In these reports, more than 15 SNPs were studied, and the most studied genetic variants were rs5275, rs5277, and rs20417.…”

“…In these reports, more than 15 SNPs were studied, and the most studied genetic variants were rs5275, rs5277, and rs20417. Therefore, our meta-analysis focused on the three SNPs and three publications [8,25,26] were excluded from further analysis since none of the three polymorphisms was presented in these articles. Of note, Cox et al validated their primary results in other two independent populations [22].…”

“…Numerous association studies regarding genes that are involved in estrogen metabolism pathway, carcinogen metabolism pathway, DNA repair pathway, and immunosurveillance pathway have been performed. Genes involved in the prostaglandin pathway could play potential roles in breast cancer susceptibility [5][6][7][8].…”

Association between NSAIDs use and breast cancer risk: a systematic review and meta-analysis

“…However, 21 papers are excluded for the following reasons: randomized double-blind placebo-control (RCT) in Women's Health Study (WHS) [15,34]; benign breast disease (BBD) women cohort [22]; survival analysis for post-menopausal women with invasive breast cancer [24] and recurrence analysis in early-stage breast cancer [29]; unavailable data in 5 studies [41][42][43][44][45] and abandoned 11 overlapping studies [16,18,19,21,23,27,28,31,[46][47][48]. Finally, 26 studies are available for this meta-analysis in association between NSAIDs use and breast cancer.…”

Polymorphisms in cycloxygenase-2 gene and breast cancer prognosis: association between PTGS2 haplotypes and histopathological features

“…A great number of studies have investigated the influence of PTGS2 single nucleotide polymorphisms (SNPs) on the risk of developing different cancer types, including esophageal [10,11], gastric [12,13], prostate [14][15][16][17][18], colorectal [19][20][21][22], lung [23,24], and breast cancer [25][26][27][28][29][30][31][32][33][34][35][36]. The results are conflicting, which may be accounted by the diversity of cancers and populations studied.…”